1. Field of the Invention
This invention relates to the field of treating patients having congestive heart failure with growth hormone (GH).
2. Description of Background and Related Art
In vitro studies have shown that chronic hypersecretion of growth hormone by implantation of a growth hormone-secreting tumor is associated with an increase in the maximum isometric force of left ventricular papillary muscle normalized per cross-sectional area and no change in both the unloaded shortening velocity of the isolated muscle and the calcium and actin-activated myosin in normal rats. This is observed despite a marked shift of the isomyosin pattern toward the low ATPase activity V3 isoform. These results suggest that growth hormone may induce a unique pattern of myocardial contraction: a normal shortening speed and an increased force generation are associated with changes in myosin phenotype that allow the cardiac muscle to function more economically. Timsit, J. et al., J. Clin. Invest. 86:507-515 (1990); Timsit, J. et al., Acta Paediatr Suppl 383:32-34 (1992).
In vitro studies from the same investigators were carried out on rat cardiac skinned fibers. These studies have demonstrated that the contractile performance of the skinned fiber from rat myocardium subjected to chronically high circulating growth hormone levels is increased. The increase in contractile performance was shown to be due to specific alterations in the properties of the contractile apparatus, including an increase in both maximal tension and myofibrillar sensitivity to calcium. Mayoux, E. et al., Circulation Research 72(1):57-64 (1993).
It has been found that left ventricular dP/dt, cardiac index, stroke index, and stroke work are significantly increased in chloralose-urethan-anesthetized rats with a transplantable growth hormone-secreting tumor. The data suggest that chronic hypersecretion of growth hormone increases cardiac output by increasing contractility in anesthetized rats. Penney, D. G. et al., Cardiovascular Research 19:270-277 (1985).
A contrary result has also been reported. Rubin, S. A. et al., J. Mol. Cell Cardiol. 22:429-438 (1990) have reported that similar chronic hypersecretion of growth hormone induced by the growth hormone-secreting tumor causes significant decreases in left ventricular contractility (maximum dP/dt) and increases in LVEDP in ketamine-anesthetized rats.
In a clinical study, it has been shown that administration of human growth hormone to normal subjects for one week increases ventricular contractility and cardiac output, as evaluated by echocardiography. Thuesen, L. et al., Dan. Med. Bull. 35:193-196 (1988).
In adults with growth hormone deficiency, growth hormone treatment produced significant increases in stroke volume and exercise capacity. These results suggest that growth hormone can improve cardiac function at rest and during exercise in the adult patients with growth hormone deficiency. Jorgensen, J. et al., Lancet i:1221-1225 (1989); Cuneo, R. et al., J. Appl. Physiol. 70:695-700 (1991); Christiansen, J. S. et al., Acta Paediatr Suppl 383:40-42 (1992).
Cuneo et al., Lancet i:838-839 (1989) have reported a very interesting case showing effects of growth hormone therapy in a patient with extremely poor cardiac function. The patient developed severe heart failure eight months after hypophysectomy for Cushing syndrome. Standard therapy including diuretics and angiotensin-converting enzyme inhibitors had little effect and cardiac transplantation was considered. As a last resort, treatment with human growth hormone, 12 IU/day s.c. was tried, with a remarkable beneficial effect. Clinical improvement and increases in myocardial contractility and cardiac output were noted.
Until now, however, effects of human growth hormone in heart failure patients without growth hormone deficiency have not been reported, to applicants' knowledge. Heart failure affects approximately three million Americans, developing in about 400,000 each year. Current therapy for heart failure is insufficient. Although angiotensin converting enzyme (ACE) inhibitors have been shown to have beneficial effects in patients with heart failure, they appear consistently unable to relieve symptoms in more than 60% of heart failure patients. In addition, they reduce mortality of heart failure only by approximately 15-20%. Therefore, there is room for improvement in the therapy of heart failure.
Accordingly it is an object of this invention to provide a method of treatment for a patient with congestive heart failure.